tbuckley/cabot-search huggingface dataset:
Guselkumab for hidradenitis suppurativa: a phase II, open-label, mode-of-action study
Authors: Koen Dudink, Klasiena Bouwman, Yanqing Chen, Samuel E DePrimo, Ernesto J Munoz-Elias, Pim Aarts, Renske Schappin, Edwin F Florencia, Bennie van Heeswijk, Lisette M Prens, Hessel H van der Zee, Errol P Prens, Kelsey R van Straalen, Barbara Horváth
Journal: British Journal of Dermatology (2023)

Abstract Background The effectiveness of available biologics for the treatment of hidradenitis suppurativa (HS) is limited. Additional therapeutic options are needed. Objectives To investigate the efficacy and mode of action of guselkumab [an anti-interleukin (IL)-23p19 monoclonal antibody] 200 mg subcutaneously every 4 weeks for 16 weeks in patients with HS. Methods An open-label, multicentre, phase IIa trial in patients with moderate-to-severe HS was carried out (NCT04061395). The pharmacodynamic response in skin and blood was measured after 16 weeks of treatment. Clinical efficacy was assessed using the Hidradenitis Suppurativa Clinical Response (HiSCR), the International Hidradenitis Suppurativa Severity Score System (IHS4), and the abscess and inflammatory nodule (AN) count. The protocol was reviewed and approved by the local institutional review board (METC 2018/694), and the study was conducted in accordance with good clinical practice guidelines and applicable regulatory requirements. Results Thirteen of 20 patients (65%) achieved HiSCR with a statistically significant decrease in median IHS4 score (from 8.5 to 5.0; P = 0.002) and median AN count (from 6.5 to 4.0; P = 0.002). The overall patient-reported outcomes did not show a similar trend. One serious adverse event, likely to be unrelated to guselkumab treatment, was observed. In lesional skin, transcriptomic analysis revealed the upregulation of various genes associated with inflammation, including immunoglobulins, S100, matrix metalloproteinases, keratin, B-cell and complement genes, which decreased in clinical responders after treatment. Immunohistochemistry revealed a marked decrease in inflammatory markers in clinical responders at week 16. Conclusions Sixty-five per cent of patients with moderate-to-severe HS achieved HiSCR after 16 weeks of treatment with guselkumab. We could not demonstrate a consistent correlation between gene and protein expression and clinical responses. The main limitations of this study were the small sample size and absence of a placebo arm. The large placebo-controlled phase IIb NOVA trial for guselkumab in patients with HS reported a lower HiSCR response of 45.0–50.8% in the treatment group and 38.7% in the placebo group. Guselkumab seems only to be of benefit in a subgroup of patients with HS, indicating that the IL-23/T helper 17 axis is not central to the pathophysiology of HS.
Author Correction: Transcriptional regulation of N6-methyladenosine orchestrates sex-dimorphic metabolic traits
Authors: David A. Salisbury, David Casero, Zhengyi Zhang, Dan Wang, Jason Kim, Xiaohui Wu, Laurent Vergnes, Aashiq H. Mirza, Paola Leon-Mimila, Kevin J. Williams, Adriana Huertas-Vazquez, Samie R. Jaffrey, Karen Reue, Jianjun Chen, Tamer Sallam
Journal: Nature Metabolism (2023)
Uptake and effectiveness of newer biologic and targeted synthetic disease-modifying antirheumatic drugs in psoriatic arthritis: results from five Nordic biologics registries
Authors: Bente Glintborg, Daniela Di Giuseppe, Johan Karlsson Wallman, Dan C Nordström, Bjorn Gudbjornsson, Merete Lund Hetland, Johan Askling, Gerdur Grondal, Tuulikki Sokka, Sella A Provan, Brigitte Michelsen, Eirik Klami Kristianslund, Lene Dreyer, Thorvardur Jon Love, Ulf Lindström
Journal: Annals of the Rheumatic Diseases (2023)

We aimed to describe the uptake of newer biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in psoriatic arthritis (PsA) in the Nordic countries and to compare their retention and effectiveness.Patients with PsA starting a b/tsDMARD in 2012-2020 in five Nordic rheumatology registers were included. Uptake and patient characteristics were described, with comorbidities identified from linkages to national patient registries. One-year retention and 6-month effectiveness (proportions achieving low disease activity (LDA) on the Disease Activity Index for PSoriatic Arthritis based on 28-joint evaluation) for the newer b/tsDMARDs (abatacept/apremilast/ixekizumab/secukinumab/tofacitinib/ustekinumab) were compared with adalimumab through adjusted regression models stratified by treatment course (first, second/third, and fourth or more).In total, 5659 treatment courses with adalimumab (56% biologic-naïve) and 4767 courses with a newer b/tsDMARD (21% biologic-naïve) were included. The uptake of newer b/tsDMARDs increased from 2014 and plateaued in 2018. Patient characteristics appeared similar across treatments at treatment start. Adalimumab was more often used as the first course and newer b/tsDMARDs more often in biologic-experienced patients. Used as a second/third b/tsDMARD, the retention rate and the proportion achieving LDA were significantly better for adalimumab (rate 65%, proportion 59%) compared with abatacept (45%, 37%), apremilast (43%, 35%), ixekizumab (LDA only, 40%) and ustekinumab (LDA only, 40%), but not significantly different from other b/tsDMARDs.Uptake of newer b/tsDMARDs occurred mainly in biologic-experienced patients. Regardless of mode of action, only a minority of patients starting a second or later b/tsDMARD course remained on drug and achieved LDA. Superior outcomes for adalimumab indicate that the positioning of newer b/tsDMARDs in the PsA treatment algorithm remains to be established.
Terminology and diagnostic criteria used in studies investigating patients with subacromial pain syndrome from 1972 to 2019: a scoping review
Authors: Adam Witten, Karen Mikkelsen, Thomas Wagenblast Mayntzhusen, Mikkel Bek Clausen, Kristian Thorborg, Per Hölmich, Kristoffer Weisskirchner Barfod
Journal: British Journal of Sports Medicine (2023)

Introduction There is no recognised terminology, nor diagnostic criteria, for patients with subacromial pain syndrome (SAPS). This is likely to cause heterogeneity across patient populations. This could be a driver of misconceptions and misinterpretations of scientific results. We aimed to map the literature regarding terminology and diagnostic criteria used in studies investigating SAPS. Materials and methods Electronic databases were searched from inception to June 2020. Original peer-reviewed studies investigating SAPS (also known as subacromial impingement or rotator cuff tendinopathy/impingement/syndrome) were eligible for inclusion. Studies containing secondary analyses, reviews, pilot studies and studies with less than 10 participants were excluded. Results 11 056 records were identified. 902 were retrieved for full-text screening. 535 were included. 27 unique terms were identified. Mechanistic terms containing ‘impingement’ are used less than before, while SAPS is used increasingly. For diagnoses, combinations of Hawkin’s, Neer’s, Jobe’s, painful arc, injection test and isometric shoulder strength tests were the most often used, though this varied considerably across studies. 146 different test combinations were identified. 9% of the studies included patients with full-thickness supraspinatus tears and 46% did not. Conclusion The terminology varied considerably across studies and time. The diagnostic criteria were often based on a cluster of physical examination tests. Imaging was primarily used to exclude other pathologies but was not used consistently. Patients with full-thickness supraspinatus tears were most often excluded. In summary, studies investigating SAPS are heterogeneous to an extent that makes it difficult, and often impossible, to compare studies.
Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials
Authors: Alain Amstutz, Benjamin Speich, France Mentré, Corina Silvia Rueegg, Drifa Belhadi, Lambert Assoumou, Charles Burdet, Srinivas Murthy, Lori Elizabeth Dodd, Yeming Wang, Kari A O Tikkinen, Florence Ader, Maya Hites, Maude Bouscambert, Mary Anne Trabaud, Mike Fralick, Todd C Lee, Ruxandra Pinto, Andreas Barratt-Due, Fridtjof Lund-Johansen, Fredrik Müller, Olli P O Nevalainen, Bin Cao, Tyler Bonnett, Alexandra Griessbach, Ala Taji Heravi, Christof Schönenberger, Perrine Janiaud, Laura Werlen, Soheila Aghlmandi, Stefan Schandelmaier, Yazdan Yazdanpanah, Dominique Costagliola, Inge Christoffer Olsen, Matthias Briel
Journal: The Lancet Respiratory Medicine (2023)
Salmonella-liberated dietary L-arabinose promotes expansion in superspreaders
Authors: Sarah J. Ruddle, Liliana M. Massis, Alyssa C. Cutter, Denise M. Monack
Journal: Cell Host & Microbe (2023)

The molecular understanding of host-pathogen interactions in the gastrointestinal (GI) tract of superspreader hosts is incomplete. In a mouse model of chronic, asymptomatic Salmonella enterica serovar Typhimurium (S. Tm) infection, we performed untargeted metabolomics on the feces of mice and found that superspreader hosts possess distinct metabolic signatures compared with non-superspreaders, including differential levels of L-arabinose. RNA-seq on S. Tm from superspreader fecal samples showed increased expression of the L-arabinose catabolism pathway in vivo. By combining bacterial genetics and diet manipulation, we demonstrate that diet-derived L-arabinose provides S. Tm a competitive advantage in the GI tract, and expansion of S. Tm in the GI tract requires an alpha-N-arabinofuranosidase that liberates L-arabinose from dietary polysaccharides. Ultimately, our work shows that pathogen-liberated L-arabinose from the diet provides a competitive advantage to S. Tm in vivo. These findings propose L-arabinose as a critical driver of S. Tm expansion in the GI tracts of superspreader hosts.
Association of Midlife Cardiovascular Health and Subsequent Change in Cardiovascular Health With Incident Cancer
Authors: Thomas Van Sloten, Eugénie Valentin, Rachel E. Climie, Omar Deraz, Elisabete Weiderpass, Xavier Jouven, Marcel Goldberg, Marie Zins, Jean-Philippe Empana
Journal: JACC CardioOncology (2023)

The commonality of risk factors between cancer and cardiovascular disease suggests that primordial prevention (preventing the onset of risk factors) is a relevant strategy for cancer prevention.This study sought to examine the association between baseline and change in the cardiovascular health (CVH) score and incident cancer.Using serial examinations of the GAZEL (GAZ et ELECTRICITE de France) study in France, we examined the associations between the American Heart Association's Life's Simple 7 CVH score (range: 0-to 14 [poor, intermediate, and ideal level of smoking, physical activity, body mass index, diet, blood pressure, diabetes status, or lipids]) in 1989/1990, their change over 7 years, and incident cancer and cardiac events up to 2015.The study population included 13,933 participants (mean age: 45.3 ± 3.4 years, 24% women). After a median follow-up of 24.8 years (Q1-Q3: 19.4-24.9 years), 2,010 participants had an incident cancer and 899 a cardiac event. The risk of cancer (any site) decreased by 9% (HR: 0.91; 95% CI: 0.88-0.93) per 1-point increase in the CVH score in 1989/1990 compared with a 20% (HR: 0.80; 95% CI: 0.77-0.83) risk reduction for cardiac events. The risk of cancer decreased by 5% (HR: 0.95; 95% CI: 0.92-0.99) per unit of change in the CVH score between 1989/1990 and 1996/1997 compared with a 7% risk reduction for cardiac events (HR: 0.93; 95% CI: 0.88-0.98). These associations remained after omitting the smoking metric from the CVH score.Primordial prevention is a relevant strategy for the prevention of cancer in the population.
Cardiovascular Toxicity of Proteasome Inhibitors: Underlying Mechanisms and Management Strategies
Authors: Georgios Georgiopoulos, Nikolaos Makris, Ageliki Laina, Foteini Theodorakakou, Alexandros Briasoulis, Ioannis P. Trougakos, Meletios-Athanasios Dimopoulos, Efstathios Kastritis, Kimon Stamatelopoulos
Journal: JACC CardioOncology (2023)

Proteasome inhibitors (PIs) are the backbone of combination treatments for patients with multiple myeloma and AL amyloidosis, while also indicated in Waldenström's macroglobulinemia and other malignancies. PIs act on proteasome peptidases, causing proteome instability due to accumulating aggregated, unfolded, and/or damaged polypeptides; sustained proteome instability then induces cell cycle arrest and/or apoptosis. Carfilzomib, an intravenous irreversible PI, exhibits a more severe cardiovascular toxicity profile as compared with the orally administered ixazomib or intravenous reversible PI such as bortezomib. Cardiovascular toxicity includes heart failure, hypertension, arrhythmias, and acute coronary syndromes. Because PIs are critical components of the treatment of hematological malignancies and amyloidosis, managing their cardiovascular toxicity involves identifying patients at risk, diagnosing toxicity early at the preclinical level, and offering cardioprotection if needed. Future research is required to elucidate underlying mechanisms, improve risk stratification, define the optimal management strategy, and develop new PIs with safe cardiovascular profiles.
Integrating neuroscience in psychiatry: a cultural–ecosocial systemic approach
Authors: Ana Gómez-Carrillo, Laurence J Kirmayer, Neil Krishan Aggarwal, Kamaldeep S Bhui, Kenneth Po-Lun Fung, Brandon A Kohrt, Mitchell G Weiss, Roberto Lewis-Fernández
Journal: The Lancet Psychiatry (2023)
3D models of neurodegeneration: implementation in drug discovery
Authors: Chloe Whitehouse, Nicola Corbett, Janet Brownlees
Journal: Trends in Pharmacological Sciences (2023)

A lack of in vitro models that robustly represent the complex cellular pathologies underlying neurodegeneration has resulted in a translational gap between in vitro and in vivo results, creating a bottleneck in the development of new therapeutics. In the past decade, new and complex 3D models of the brain have been published at an exponential rate. However, many novel 3D models of neurodegeneration overlook the validation and throughput requirements for implementation in drug discovery. This therefore represents a knowledge gap that could hinder the translation of these models to drug discovery efforts. We review the recent progress in the development of 3D models of neurodegeneration, examining model design benefits and validation techniques, and discuss opportunities and standards for 3D models of neurodegeneration to be implemented in drug discovery and development.
Impact of Age at Diagnosis on Cardiotoxicity in High-Grade Osteosarcoma and Ewing Sarcoma Patients
Authors: Julius C. Heemelaar, Frank M. Speetjens, Ahmed A.M. al Jaff, Richard E. Evenhuis, Elissa A.S. Polomski, Bart J.A. Mertens, J. Wouter Jukema, Hans Gelderblom, Michiel A.J. van de Sande, M. Louisa Antoni
Journal: JACC CardioOncology (2023)

Osteosarcoma and Ewing sarcoma patients face a significant risk of cardiotoxicity as defined by left ventricular dysfunction and heart failure (HF).This study sought to evaluate the association between age at sarcoma diagnosis and incident HF.A retrospective cohort study was performed at the largest sarcoma center in the Netherlands among patients with an osteosarcoma or Ewing sarcoma. All patients were diagnosed and treated over a 36-year period (1982-2018) and followed until August 2021. Incident HF was adjudicated through the universal definition of heart failure. Determinants including age at diagnosis, doxorubicin dose, and cardiovascular risk factors were entered as fixed or time-dependent covariates into a cause-specific Cox model to assess their impact on incident HF.The study population consisted of 528 patients with a median age at diagnosis of 19 years (Q1-Q3: 15-30 years). Over a median follow-up time of 13.2 years (Q1-Q3: 12.5-14.9 years), 18 patients developed HF with an estimated cumulative incidence of 5.9% (95% CI: 2.8%-9.1%). In a multivariable model, age at diagnosis (HR: 1.23; 95% CI: 1.06-1.43) per 5-year increase, doxorubicin dose per 10-mg/m2 increase (HR: 1.13; 95% CI: 1.03-1.24), and female sex (HR: 3.17; 95% CI: 1.11-9.10) were associated with HF.In a large cohort of sarcoma patients, we found that patients diagnosed at an older age are more prone to develop HF.
Screening for Coronary Artery Disease in Cancer Survivors
Authors: Ragani Velusamy, Mark Nolan, Andrew Murphy, Paaladinesh Thavendiranathan, Thomas H. Marwick
Journal: JACC CardioOncology (2023)

Coronary artery disease (CAD) is an important contributor to the cardiovascular burden in cancer survivors. This review identifies features that could help guide decisions about the benefit of screening to assess the risk or presence of subclinical CAD. Screening may be appropriate in selected survivors based on risk factors and inflammatory burden. In cancer survivors who have undergone genetic testing, polygenic risk scores and clonal hematopoiesis markers may become useful CAD risk prediction tools in the future. The type of cancer (especially breast, hematological, gastrointestinal, and genitourinary) and the nature of treatment (radiotherapy, platinum agents, fluorouracil, hormonal therapy, tyrosine kinase inhibitors, endothelial growth factor inhibitors, and immune checkpoint inhibitors) are also important in determining risk. Therapeutic implications of positive screening include lifestyle and atherosclerosis interventions, and in specific instances, revascularization may be indicated.
Racial and Ethnic Disparities in All-Cause and Cardiovascular Mortality Among Cancer Patients in the U.S.
Authors: Cenjing Zhu, Tiantian Shi, Changchuan Jiang, Baoqiong Liu, Lauren A. Baldassarre, Stuart Zarich
Journal: JACC CardioOncology (2023)

With improved cancer survival, death from noncancer etiologies, especially cardiovascular disease (CVD) mortality, has come more into focus. Little is known about the racial and ethnic disparities in all-cause and CVD mortality among U.S. cancer patients. This study sought to investigate racial and ethnic disparities in all-cause and CVD mortality among adults with cancer in the United States. Using the Surveillance, Epidemiology, and End Results (SEER) database from years 2000 to 2018, all-cause and CVD mortality among patients ≥18 years of age at the time of initial malignancy diagnosis were compared by race and ethnicity groups. The 10 most prevalent cancers were included. Cox regression models were used to estimate adjusted HRs for all-cause and CVD mortality using Fine and Gray's method for competing risks, as applicable. Among a total of 3,674,511 participants included in our study, 1,644,067 (44.7%) died, with 231,386 (6.3%) deaths as a result of CVD. After adjusting for sociodemographic and clinical characteristics, non-Hispanic (NH) Black individuals had both higher all-cause (HR: 1.13; 95% CI: 1.13-1.14) and CVD (HR: 1.25; 95% CI: 1.24-1.27) mortality, whereas Hispanic and NH Asian/Pacific Islander had lower mortality than NH White patients. Racial and ethnic disparities were more prominent among patients 18 to 54 years of age and those with localized cancer. Significant racial and ethnic differences exist in both all-cause and CVD mortality among U.S. cancer patients. Our findings underscore the vital roles of accessible cardiovascular interventions and strategies to identify high-risk cancer populations who may benefit most from early and long-term survivorship care.
Influence of melanoma type on incidence and downstream implications of cutaneous immune-related adverse events in the setting of immune checkpoint inhibitor therapy
Authors: Nga Nguyen, Guihong Wan, Pearl Ugwu-Dike, Nora A. Alexander, Neel Raval, Shijia Zhang, Ruple Jairath, Jordan Phillipps, Bonnie Leung, Katie Roster, Jayhyun Seo, Chenyue Lu, Kimberly Tang, Min Seok Choi, Mia S. DeSimone, Nicholas Theodosakis, Munachimso Amadife, Nevada Cox, Thomas K. Le, Feng Liu, Wenxin Chen, Xue Bai, Genevieve Boland, David Liu, Marc S. Hurlbert, Nicole LeBoeuf, Kerry L. Reynolds, Kun-Hsing Yu, Hensin Tsao, Maryam Asgari, Alexander Gusev, Shawn G. Kwatra, Yevgeniy R. Semenov
Journal: Journal of the American Academy of Dermatology (2023)
Socioeconomic and Racial Disparities in Vision Care Access and Impairment Among United States Children
Authors: Muhammad Z. Chauhan, Abdelrahman M. Elhusseiny, Brita S. Rook, Esaa S. Samarah, Sami H. Uwaydat, Ahmed B. Sallam, Paul H. Phillips
Journal: Ophthalmology (2023)
Diabetes Mellitus Impacts on the Performance of Hepatocellular Carcinoma Risk Scores in Chronic Hepatitis B Patients
Authors: Terry Cheuk-Fung Yip, Vincent Wai-Sun Wong, Mandy Sze-Man Lai, Jimmy Che-To Lai, Yee-Kit Tse, Lilian Yan Liang, Vicki Wing-Ki Hui, Henry Lik-Yuen Chan, Grace Lai-Hung Wong
Journal: Clinical Gastroenterology and Hepatology (2023)
Genetic insights into the neurobiology of anxiety
Authors: Maija-Kreetta Koskinen, Iiris Hovatta
Journal: Trends in Neurosciences (2023)

Anxiety and fear are evolutionarily conserved emotions that increase the likelihood of an organism surviving threatening situations. Anxiety and vigilance states are regulated by neural networks involving multiple brain regions. In anxiety disorders, this intricate regulatory system is disturbed, leading to excessive or prolonged anxiety or fear. Anxiety disorders have both genetic and environmental risk factors. Genetic research has the potential to identify specific genetic variants causally associated with specific phenotypes. In recent decades, genome-wide association studies (GWASs) have revealed variants predisposing to neuropsychiatric disorders, suggesting novel neurobiological pathways in the etiology of these disorders. Here, we review recent human GWASs of anxiety disorders, and genetic studies of anxiety-like behavior in rodent models. These studies are paving the way for a better understanding of the neurobiological mechanisms underlying anxiety disorders.